Table 1.

Changes associated with blood–brain barrier (BBB) breakdown in normal aging, Alzheimer's disease (AD), and vascular dementia (VaD).

BBB elements	Characteristics	Aging	References	AD	References	VaD	References
ECs	• Endothelium degeneration, Mitochondrial content decrease, pinocytotic vesicle increase • Microvessel density decrease	Yes	(Bell and Zlokovic, 2009; Grinberg and Thal, 2010; Richardson et al., 2012; Rouhl et al., 2012; Sagare et al., 2012)	Yes	(Salmina et al., 2010; Villar-Vesga et al., 2020; Chacón-Quintero et al., 2021; González-Molina et al., 2021)	Yes	(Wardlaw et al., 2003; Zhang et al., 2014; Rajani et al., 2018; Wang et al., 2018; Tayler et al., 2021; Zhu et al., 2021)
Extracellular components	• Increase (accumulation)	Yes	(Brown and Thore, 2011)	Yes	(Zlokovic, 2011; Hawkes et al., 2013; Morris et al., 2014; Howe et al., 2020)	Yes	(Ueno et al., 2002; Rosenberg, 2017)
Basal lamina	• Thickness increase	Yes	(Grinberg and Thal, 2010; Richardson et al., 2012; Rouhl et al., 2012)	Yes	(Zlokovic, 2011; Morris et al., 2014)	Yes	(Ueno et al., 2002; Iadecola, 2013; Rosenberg, 2017)
Pericytes	• Pericytes number decrease • PDGFRβ in CSF increase	Yes	(Bell et al., 2010; Montagne et al., 2015; Sagare et al., 2015; Duncombe et al., 2017; Erdo et al., 2017; Goodall et al., 2018; Nation et al., 2019)	Yes	(Sengillo et al., 2013; Halliday et al., 2016; Montagne et al., 2018; Miners et al., 2019; Uemura et al., 2020)	Yes	(Iadecola, 2013; Montagne et al., 2018; Yang et al., 2018; Uemura et al., 2020)
Astrocytes	• Vascular coverage reduction • GFAP upregulation • AQP4 downregulation	Yes	(Middeldorp and Hol, 2011; Duncombe et al., 2017; Goodall et al., 2018; Heithoff et al., 2021)	Yes	(Abbott et al., 2006; Yang Y. et al., 2011; Kimbrough et al., 2015; Ahmad et al., 2019)	Yes	(Wardlaw et al., 2003; Iadecola, 2013; Saggu et al., 2016; Price et al., 2018; Wang et al., 2018; Tayler et al., 2021)
Microglia	• Release of neurotoxins • Changes to amoeboid morphology	Yes	(Kettenmann et al., 2011; Ronaldson and Davis, 2012)	Yes	(Zotova et al., 2011; Hansen et al., 2018; Ahmad et al., 2019; Hemonnot et al., 2019; Leng and Edison, 2020)	Yes	(Wu et al., 2016; Wang et al., 2018; Tayler et al., 2021)
Neurons	• Synaptic plasticity diminishment • Impaired long-term potentiation • Dysfunctional neurogenesis • Elevation in apoptosis • Neurodegeneration	Yes	(Buschini et al., 2011; Blau et al., 2012; Cerbai et al., 2012; Lucke-Wold et al., 2014)	Yes	(Crews and Masliah, 2010; Arendt et al., 2015; Vasic et al., 2019; Bartels et al., 2020)	Yes	(Saggu et al., 2016; Montagne et al., 2018; Wang et al., 2018; Tayler et al., 2021; Zhu et al., 2021)
Tight junctions Proteins	• CLDN5, OCLN, ZO-1 expression decreases and BBB integrity reduction, BBB permeability increase	Yes	(Bake et al., 2009; Wang et al., 2011; Lassman et al., 2012; Elahy et al., 2015)	Yes	(Biron et al., 2011; Cuevas et al., 2019; Yamazaki et al., 2019)	Yes	(Wang et al., 2018; Yang et al., 2018)
Transporter dysfunctions	• Influx transporter: Glut1 expression decrease, glucose uptake reduction • Efflux Transporter: LRP-1 (human) and P-gp expression decrease (mouse)	Yes	(van Assema et al., 2012; Ding et al., 2013; Jiang et al., 2013; Chiu et al., 2015; Ramanathan et al., 2015; Hoffman et al., 2017; Patching, 2017; Sweeney et al., 2019a)	Yes	(Owen et al., 2010; Jaeger et al., 2011; Ding et al., 2013; Chiu et al., 2015; Ramanathan et al., 2015; Winkler et al., 2015; Halliday et al., 2016; Patching, 2017; Yu et al., 2020; Kyrtata et al., 2021)	Yes	(Hase et al., 2019)
Circulating factors	• ASM (acid sphingomyelinase), sphingomyelin phosphodiesterase 1 (Smpd1) upregulation	Yes	(Park et al., 2018; Wangb et al., 2019)	*		*
Other factors	• SIRT1 expression decrease	Yes	(Chang and Guarente, 2014; Imai and Guarente, 2014; Stamatovic et al., 2019)	*		*

“*” shows no obvious research studies are found related to AD and VaD.